Structure-Based Drug Design
of Pf DHODH Inhibitors
as Antimalarial Agents
Shweta Bhagat, Anuj Gahlawat and Prasad V. Bharatam
Abstract Structure-based drug design (SBDD) is being efficiently used for the
design of antimalarial agents. It is a very effective tool for challenges like drug
selectivity and resistance. Over the past decade, a considerable number of druggable targets have been explored—these include Na
+ ATPase 4 ion channel,
cytochrome bc1, mitochondrial electron transport chain, phosphatidylinositol
4-kinase (PfPI4 K), dihydroorotate dehydrogenase, hemozoin formation, dihydrofolate reductase inhibitors, etc. Among these, Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) is a new and very promising target.
PfDHODH has shown considerable potential in arresting growth of the parasite at
blood stage by inhibiting pyrimidine biosynthesis. This chapter provides a review
of all the SBDD efforts for the development of inhibitors against PfDHODH.
Keywords Plasmodium falciparum Á Structure-based drug design
Molecular docking Á Virtual screening Á Dihydroorotate dehydrogenase
Selectivity
List of Abbreviations
ACT
Aspartate carbamoyltransferase
ADME
Absorption, distribution, metabolism, and excretion
CoMFA
Comparative molecular field analysis
CoMSIA
Comparative molecular similarity index analysis
CoQ
Coenzyme Q (Ubiquinone)
CTP
Cytidine triphosphate
DBP
Docking-based pharmacophore
DHOtase
Dihydroorotase
S. Bhagat Á P. V. Bharatam (&)
Department of Medicinal Chemistry, National Institute of Pharmaceutical
Education and Research (NIPER), S.A.S. Nagar 160062, Punjab, India
e-mail: pvbharatam@niper.ac.in
A. Gahlawat
Department of Pharmacoinformatics, National Institute of Pharmaceutical
Education and Research (NIPER), S.A.S. Nagar 160062, Punjab, India
© Springer Nature Switzerland AG 2019
C. G. Mohan (ed.), Structural Bioinformatics: Applications in Preclinical Drug
Discovery Process, Challenges and Advances in Computational Chemistry
and Physics 27, https://doi.org/10.1007/978-3-030-05282-9_6
177
of Pf DHODH Inhibitors
as Antimalarial Agents
Shweta Bhagat, Anuj Gahlawat and Prasad V. Bharatam
Abstract Structure-based drug design (SBDD) is being efficiently used for the
design of antimalarial agents. It is a very effective tool for challenges like drug
selectivity and resistance. Over the past decade, a considerable number of druggable targets have been explored—these include Na
+ ATPase 4 ion channel,
cytochrome bc1, mitochondrial electron transport chain, phosphatidylinositol
4-kinase (PfPI4 K), dihydroorotate dehydrogenase, hemozoin formation, dihydrofolate reductase inhibitors, etc. Among these, Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) is a new and very promising target.
PfDHODH has shown considerable potential in arresting growth of the parasite at
blood stage by inhibiting pyrimidine biosynthesis. This chapter provides a review
of all the SBDD efforts for the development of inhibitors against PfDHODH.
Keywords Plasmodium falciparum Á Structure-based drug design
Molecular docking Á Virtual screening Á Dihydroorotate dehydrogenase
Selectivity
List of Abbreviations
ACT
Aspartate carbamoyltransferase
ADME
Absorption, distribution, metabolism, and excretion
CoMFA
Comparative molecular field analysis
CoMSIA
Comparative molecular similarity index analysis
CoQ
Coenzyme Q (Ubiquinone)
CTP
Cytidine triphosphate
DBP
Docking-based pharmacophore
DHOtase
Dihydroorotase
S. Bhagat Á P. V. Bharatam (&)
Department of Medicinal Chemistry, National Institute of Pharmaceutical
Education and Research (NIPER), S.A.S. Nagar 160062, Punjab, India
e-mail: pvbharatam@niper.ac.in
A. Gahlawat
Department of Pharmacoinformatics, National Institute of Pharmaceutical
Education and Research (NIPER), S.A.S. Nagar 160062, Punjab, India
© Springer Nature Switzerland AG 2019
C. G. Mohan (ed.), Structural Bioinformatics: Applications in Preclinical Drug
Discovery Process, Challenges and Advances in Computational Chemistry
and Physics 27, https://doi.org/10.1007/978-3-030-05282-9_6
177